Sickle Cell Disease and the Eye: Old and New Concepts

SURVEY OF OPHTHALMOLOGY

VOLUME 55  NUMBER 4  JULY–AUGUST 2010

MAJOR REVIEW

Sickle Cell Disease and the Eye: Old and New Concepts Mohammed Elagouz, MD,1,2 Sreedhar Jyothi, MRCOphth,1 Bhaskar Gupta, MRCOphth,1 and Sobha Sivaprasad, DM, MS, FRCS1 1

Laser and Retinal Research Unit, Department of Ophthalmology, King’s College Hospital, London, United Kingdom; and 2Department of Ophthalmology, Sohag University Hospital, Sohag, Egypt

Abstract. The pathophysiology of sickle cell disease is not limited to abnormal red blood cells. The clinical manifestations of sickle cell disease include complex pathways and processes such as endothelial activation, inflammation, bioavailability of nitric oxide, oxidative stress, and the adhesiveness of a variety of blood cells. Increasingly, distinct subphenotypes and genetic modifiers of sickle cell disease are being recognized. We apply recent advances in sickle cell disease to ocular biology to highlight translational research in this field and encourage additional studies on the ocular manifestations of sickle cell disease. (Surv Ophthalmol 55:359--377, 2010. Ó 2010 Elsevier Inc. All rights reserved.) Key words. animal studies  genetic modifiers  ocular manifestations retinopathy  sickle cell disease  sickle cell retinopathy

I. Introduction



proliferative sickle

A. GENETICS OF SICKLE CELL DISEASE

In each red blood cell two b-globin proteins combine with two a-globin proteins and a central heme molecule to form adult hemoglobin (Hb A). SCD is caused by a single point mutation that substitutes valine for glutamic acid at the sixth position in the b-globin chain, resulting in sickle hemoglobin (Hb S). The b-globin gene, which is on the short arm of chromosome 11, is a member of the globin family of oxygen transport genes.5 SCD inheritance is autosomal recessive, so either two copies of Hb S or one copy of Hb S plus another b-globin variant, such as Hb C, caused by a glutamic acid to lysine mutation, are required for disease expression. Individuals with homozygous SCD have two copies of this variant allele, a genotype denoted SS, and the primary hemoglobin in their red blood

The phenotypic heterogeneity of sickle cell disease (SCD) ranges from hemolytic anemia and chronic vasculopathy with acute painful crises to a multitude of organ-specific manifestations of varying severity. The exact cause of this diversity of clinical features remains unclear, but recent advances in the understanding of clinical SCD indicate that the pathophysiology of this disease is complex and multifaceted. Factors that influence the disease process include genetic variation, the proportion of sickled cells, endothelial cell activation, inflammation, oxidative stress, and hypoxia-induced angiogenesis.113 We hope that reviewing current aspects of sickle cell retinopathy (SCR) and other ocular manifestations of SCD will aid translational research on this organ-specific SCD complication. 359 Ó 2010 by Elsevier Inc. All rights reserved.

0039-6257/$--see front matter doi:10.1016/j.survophthal.2009.11.004

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cells is sickle hemoglobin. Individuals with other types of SCD are compound heterozygotes, possessing one Hb S variant allele plus one allele of another b-globin gene variant, such as Hb C or the allele for Hb b-thalassemia, that results in heterozygous hemoglobin S disease. These are designated sickle cell trait, or AS; heterozygous sickle cell-hemoglobin C disease, or SC; and sickle b-thalassemia disease.200 The absence of beta-globin component of hemoglobin is referred to as beta-zero (B0) thalassemia and a reduced amount of beta-globin is called beta-plus (Bþ) thalassemia. B. PREVALENCE OF SICKLE CELL DISEASE

About 250,000 children are born worldwide every year with SCD. Approximately 60,000 people in the USA and 10,000 in the United Kingdom presently have the disease, making it one of the most prevalent genetic disorders.100 Populations of African descent exhibit the highest frequency of genotypes associated with Hb S; however, people of Mediterranean, Caribbean, South and Central American, Arab, and East Indian descent also have high frequencies of at-risk genotypes. Hb S carriers are protected from malarial infection, and this protection probably led to the high frequency of Hb S in populations of African and Mediterranean ancestry.8 Despite this advantage, SCD is associated with significant morbidity and mortality. About 8% of black Americans have AS, or sickle cell trait, with a hemoglobin composition that is usually 35--40% Hb S and 55--60% Hb A. AS is not associated with increased morbidity or mortality. An estimated 0.15% of black American children have SS type disease, which manifests as severe hemolytic anemia with hematocrit values between 18--30%. Symptoms usually do not develop until after the age of 6 months, when fetal Hb is replaced by Hb S. Retarded growth and increased susceptibility to infection are the primary manifestations.73 Prevalence among adults is much lower because of the decreased life expectancy.21 The increased morbidity and mortality of SCD is primarily due to recurrent vaso-occlusive episodes that can affect any organ, but most frequently the lungs, kidneys, liver, skeleton, and skin.120 Individuals with sickle cell-hemoglobin C disease, or SC, are doubly heterozygous, and the hemoglobin composition is usually 50% Hb S and 50% Hb C. The frequency for the Hb C allele is only about onefourth that of the Hb S allele, but SC-type disease is nearly as prevalent among adults as SS-type disease, because of the relatively normal life expectancy of persons with SC-type disease. These patients usually have a mild to moderate hemolytic anemia, with occasional painful crises and organ infarcts.21

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Sickle b-thalassemia patients are usually found in Mediterranean and central African countries, and their hemoglobin composition is usually 60--90% Hb S and 10--30% Hb F. In some forms of sickle bthalassemia, Hb A represents 10--30%.21 Finally, hemoglobin S/O (Arab) is a rare variant, characterized by the presence of two variant b-globin chains, glutamic acid to valine at position six (Hb S), and glutamic acid to lysine at position 121 (Hb O [Arab]). Although these alleles cause a severe sickling hemoglobinopathy, the manifestations are similar to SS disease, and retinopathy is infrequent.234 In 2008, in order to determine the prevalence and age of onset of clinically significant retinopathy in pediatric patients,74 Gill and Lam studied 263 pediatric SCD patients with a maximum age of 18 years (163 patients with SS genotype, 73 patients with SC genotype, and 27 patients with b-thalassemia). They found that proliferative sickle cell retinopathy (PSR) was rare (8.2% in SC genotype, 0.6% in the SS genotype, and no cases in b-thalassemia), but when it occurred, the mean age of onset was 13.7 years (median 13 years, range 9--18) in the SC genotype and 16 years in the SS genotype. Neither sex nor the presence of systemic manifestations were predictive for prevalence or age of onset of retinopathy. The authors recommend that screening for retinopathy begin at 9 years for SC patients and at 13 years for SS and Sb-thalassemia patients. They further suggest that serial examinations may be done biennially for eyes with normal findings, and that fluorescein angiography be performed on eyes with abnormal examinations, with followup as necessary. Babalola and Wambebe examined 90 patients with SCD (88 with the SS genotype and 2 with the SC genotype), aged 5--36 years,10 and found that 24% had some form of SCD-related posterior segment pathology, 5.6% of which was preproliferative or proliferative. They recommended that children with SCD should, from the age of 10, undergo dilated fundus examination, preferably with fluorescein angiography, at least biennially. From the age of 20, they suggest annual eye examinations. C. GENETIC MODIFIERS

Although SCD is a prototypically monogenic disease, it shows clinical heterogeneity, probably because of multiple gene interactions and environmental effects. The primary genetic determinants are the underlying genotypes, with SS generally being more severe than SC, but patients with the same b-globin genotypes may have very different patterns of clinical expression. Extensive biochemical and pathophysiological studies over the last 50 years have identified major genetic modifiers for

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SCD.163 One is the innate ability to produce Hb F and the other is the presence of b-globin cluster haplotypes and co-inheritance of b-thalassemia. The influence of these modifiers has been validated by family and population based studies.141 High levels of Hb F are associated with reduced severity of the clinical course of SCD.221 Some individuals have persistence of expression of the Hb F locus.26,131 Some therapies for SCD, such as treatment with hydroxyurea, act by raising Hb F levels. Another modulating factor is the presence of b-globin cluster haplotypes. Like the main b-globin gene, these are located on chromosome 11.5 The haplotypes are named after the geographic regions of Africa and the Middle East where they predominate.142 Different haplotypes result in different levels of hemoglobin and Hb F,181 and these levels correlate with the clinical manifestations of SCD.221 Among the three most common b-globin haplotypes, the Senegal haplotype is associated with the most benign form of SCD, followed by the Benin haplotype. The Central African Republic haplotype is associated with the most severe form.181 In Africa as well as in the United States, sickle cell patients with the Central African Republic haplotype have a two-fold increase in risk of complications and early mortality compared to sickle cell patients with other haplotypes.181 The co-existence of b-thalassemia also appears to be protective against some sickle cell complications.141 Although well-established, these modifiers do not explain the full clinical spectrum of SCD. Candidate gene studies have also identified new modifiers, including single nucleotide polymorphisms in bone morphogenetic protein receptor 2; the TGF-b superfamily that is linked to endothelial dysfunction; genes associated with nitric oxide (NO) biology; the MTHFR 677T allele that is associated with vascular complications of SCD; and genes for Factor XIII, aquaporin (AQP1), and adhesion molecules that are linked to priapism.48,93 The HLA-DRB1*03 allele is associated with susceptibility to stroke in SCD patients, whereas the HLA-DRB1*02 allele has a protective effect.105 The elucidation of additional genetic variants and mechanisms responsible for the phenotypic variability of SCD will be important for clinical management, and may improve the accuracy of disease severity predictions and facilitate risk stratification.104,210 D. GENETIC MODIFIERS AND OCULAR DISEASE

Unfortunately, little is known about the role of genetic and environmental modifiers in the ocular manifestations of SCD. PSR is the major sightthreatening complication of sickle eye disease,

reaching frequencies as high as 70% in SC-disease, although most SC subtypes have a mild systemic clinical course with near normal hematology and infrequent vaso-occlusive episodes. Patients with SS disease generally have frequent vaso-occlusion and a severe systemic clinical course, and PSR was previously thought to be less frequent in these patients. However, recent studies from Africa have revealed that PSR is more frequent than previously thought, possibly because patients with SS disease are living longer.11,50,223 Documented ocular pathology associated with Hb AS includes retinal hemorrhage and exudates, angioid streaks, chorioretinal infarctions, chorioretinitis, vitreous hemorrhage, central retinal artery occlusion and PSR.169,215 In the majority of reported cases, these complications occurred in patients with concomitant systemic disease such as hypertension, tuberculosis, diabetes, sarcoidosis, syphilis, or rheumatoid arthritis. A few cases were associated with blunt ocular trauma in the absence of systemic disease,151 suggesting a role for environmental modifiers. Many ocular findings reported in sickle cell trait may be coincidental in view of the large number of patients that have this finding. E. ANIMAL MODELS OF SICKLE CELL DISEASE

Transgenic animal models of SCD have contributed significantly to understanding of the disease spectrum15,136,165 and the pathophysiology of SCD, as well as to the development of antisickling drugs and antisickling gene therapy.55 Models include sickle cell transgenic mouse lines that express only human globin chains,55,172 and lines that express a combination of murine and human globins, such as the SAD-1, Costantini-Fabry-Nagel (NYC1), and SþS-Antilles models.53,54,224 NYC1 mice are the best model for studying retinal manifestations, because they have a mild phenotype that allows ease of breeding, but a more severe phenotype can be induced by hypoxia. The NYC1 model is produced by simultaneously injecting locus control region constructs mLCR-bs and mLCR-aH into C57BL/6J mice, and breeding the transgenic animals with mice that are homozygous for the mouse bmajor deletion to produce an aHbs[bMDD] transgenic mouse.54 The mice exhibit retinal and choroidal pathological changes similar to human SCD, including vaso-occlusion from loss of precapillary arterioles, capillaries and venules, intraretinal and extraretinal neovascularisation of venous origin, choroidal neovascularisation, pigmented lesions resembling human sunburst lesions, and photoreceptor cell loss.138 The mice, however, differ from human SCD in that choroidal neovascularisation

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and photoreceptor loss as the result of choroidal nonperfusion are more common than in humans, where retinal vascular changes are more prevalent. Retinal vascular changes in the mice are also more central and manifest with fewer hemorrhages compared to the human disease.138

II. Molecular Biology of Sickle Cell Disease Although SCD is historically thought of as a red blood cell disorder, the pathophysiology of vasoocclusion and tissue ischemia involve interactions between red blood cells, the endothelium, vasoactive factors, and other blood cells. The molecular biology of SCD can be classified into specific red blood cell effects and extrinsic causes,141 although these classifications do not always apply to the spectrum of SCD symptoms.120 Recently, the clinical manifestations of SCD were broadly classified into two categories by pathophysiology. The category of hemolytic subphenotypes includes pulmonary hypertension, priapism, leg ulcers, and stroke, all of which are thought to be the biological consequences of hemolysis because of reduced NO bioavailability. The category of vasoocclusive phenotypes includes retinopathy, osteonecrosis, and renal failure, which may represent the effects of chronic vasculopathy induced by endothelial activation, procoagulant, and proangiogenic molecules.161 A. FACTORS AFFECTING RED BLOOD CELLS

When SCD red blood cells are exposed to hypoxia, hyperosmolarity, or acidosis, the deoxygenated Hb S polymerizes within the erythrocytes and renders the sickled red blood cells (sRBCs) rigid and nondeformable.119 The polymerization does not occur immediately after deoxygenation, so most sRBCs pass through the capillary bed before sickling, making microvascular occlusion uncommon.101,162 Therefore, Hb polymerization is not likely to be the exclusive cause of microvascular occlusion, with factors that increase capillary transit time also of importance. The ability of sRBCs to maintain hydration decreases with increasing deoxygenation because of activation of the Gardos channel, which is a Ca2þ-activated channel that exports Kþ accompanied by water, resulting in cellular dehydration.161,164 The sRBCs also have increased adhesion to endothelial and subendothelial matrix proteins such as laminin, adding to the damage from the mechanical obstruction of the blood vessels.52,97 Over the last decades, surface adhesion molecules and markers of the adhesion process in SCD have been the focus of considerable research.91,95,98,111,213,214

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Adhesion molecules expressed in sRBCs include integrin a4b1, CD36, band 3 protein, sulfated glycolipid, lutheran protein, phosphatidylserine, and integrin-associated protein.213,214,232 Proadhesive sRBCs bind to endothelial cell P-selectin, E-selectin, intercellular adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM-1), CD36 and integrins, leading to the activation of the endothelium.97,98,111,123,213 Reticulocytes, or immature red blood cells, are also increased in SCD and express adhesion molecules such as a4b1 and CD36. Lutty et al demonstrated that the mechanisms by which sRBCs are retained in the retina and choroid are similar, in that hypoxia causes mechanical retention of the dense sRBCs, and that adhesion of reticulocytes occurs after exposure to tumor necrosis factor alpha (TNF-a) exposure and this effect is inhibited by an antagonist to the integrin VLA-4.135,137,140,226 B. EXTRINSIC FACTORS

Recent evidence indicates that SCD is also an inflammatory condition, a procoagulant condition, and a vasculopathy, and that these extrinsic factors also contribute to the phenotypic diversity of the disease. 1. Inflammation and Endothelial Cell Activation White blood cells also contribute to the vasoocclusive process, with a leukocyte count of 15,000 cells/dl considered a significant independent risk factor for early death.96 Polymorphonuclear leucocytes (PMNs) from sickle cell patients are less deformable, and therefore, less filterable than PMNs from nonsickle cell patients,29 and activated PMNs are increased in sickle cell patients.122 Recent evidence suggests that PMNs can bind to sRBCs, and this association further activates these red blood cells. PMNs also adhere to the vascular endothelium through adhesion molecules including ICAM-1, VCAM-1, E-selectin, and P-selectin.123 Increased levels of soluble ICAM-1 have been reported in the sera of SCD patients, and both steady-state SCD patients and patients experiencing acute chest syndrome have increased levels of soluble VCAM-1.194,212 The potent neutrophil chemokine interleukin (IL)-8 is also elevated in the sera of SCD subjects during crisis.46 Cytokines such as TNF-a and IL-1a upregulate the expression of leukocyte adhesion molecules in endothelial cells, and both TNFa and IL-1a are elevated in the sera of patients with steady-state SCD,63,134,143 possibly because of lowlevel inflammation caused by abnormal adhesion of sRBCs to endothelial cells in the microvasculature,

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resulting in ischemia and subsequent tissue damage.156 Mathews et al148 reported that SCD retinas showed increased immunoreactivity against ICAM1, VCAM-1, and P-selectin, compared to controls. The highest ICAM and P-selectin immunoreactivities were associated with intraretinal vessels adjacent to the preretinal neovascular formation in subjects with proliferative retinopathy. VCAM-1 immunoreactivity was highest in intraretinal vessels adjacent to the sea fan, when the sea fan was still in statu nascendi. Fully formed, older sea fans had the highest levels of VCAM-1, and the increase in immunoreactivity was concomitant with an increase in intraretinal PMNs. The number of intraretinal PMNs increased with disease progression, eventually reaching three times the number seen in controls. The sea fan observed to have the highest VCAM-1 immunoreactivity had 20 times more PMNs than the rest of the retina. The authors concluded that leukocyte adhesion mediated by specific adhesion molecules might have an important role in the vasoocclusive phase of sickle cell retinopathy, and in autoinfarction of sea fan formations. Monocytes also activate the endothelium by releasing proinflammatory cytokines such as TNFa and IL-1a. Sickle monocytes also express increased CD11b on the surface, and TNF-a and IL-1a in the cytoplasm, indicating an activated state. Circulating endothelial cells with increased expression of ICAM1, VCAM and tissue factor are also increased in SCD patients.16,96 2. Pro-coagulant Pathways Activated platelets secrete thrombospondin and the cytokine IL-1 and form platelet-monocyte aggregates that induce expression of P-selectin in endothelial cells.18 Endothelial cell activation by these multiple mechanisms leads to loss of vascular integrity, expression of leukocyte adhesion molecules, changes in the cell surface from antithrombotic to prothrombotic, excessive cytokine production, and upregulation of human leukocytic antigen. Furthermore, contraction of the activated endothelial cells leads to exposure of extracellular matrix proteins, such as thrombospondin, laminin, and fibronectin, and their participation in adhesive interactions with plasma bridging molecules released from endothelial cells such as von Willebrand factor (vWF) ultimately results in vaso-occlusion and local tissue ischemia.95,98 3. Angiogenesis The role of the formation of new blood vessels from the existing vasculature in the pathophysiology of SCD is relatively unexplored. Vascular endothelial

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growth factor (VEGF), a mitogen derived from arteries, veins, and lymphatics,58 contributes to increased endothelial cell adhesiveness by increasing the expression of the cell adhesion molecules ICAM-1 and VCAM-1.133,179 VEGF is elevated in the plasma of patients with steady-state SCD, and is significantly elevated during vaso-occlusive events.91 VEGF is a likely candidate for a stimulating factor in sea fan formation because its expression is upregulated by hypoxia.204 VEGF also increases vascular permeability, and sea fans profusely leak fluorescein dye.81 Cao et al compared the immunoreactivity for VEGF and basic fibroblast growth factor (bFGF) in the retinas of SCD subjects and controls,22 and found the highest immunoreactivity in feeder and preretinal vessels of sea fans. The most prominent immunoreactivity was in vascular endothelial cells. In retinal vessels, VEGF and bFGF immunoreactivities were higher in both proliferative and nonproliferative sickle cell subjects than in controls. In the sickle cell retina, no immunoreactivity to angiogenic factor was detected in the non-perfused periphery, and no significant differences were seen for bFGF or VEGF immunoreactivity between the perfused retina and the border of perfused and non-perfused areas. The authors therefore concluded that VEGF and bFGF are associated with sea fan formation in sickle cell retinopathy. Recently, placental growth factor was found to be produced by erythroblasts, and to activate monocytes in SCD. The levels of placental growth factor are higher in the plasma of SCD patients than in controls, and levels correlate with disease severity.179 Angiopoietin-1 and angiopoietin-2 (Ang-1, Ang-2) are members of another family of vascular growth factor, which interact with the endothelial cellspecific tyrosine kinase receptor Tie-2.142 Ang-1 acts via the Tie-2 receptor to remodel primitive vessels and to maintain and stabilize mature vessels by promoting interaction between endothelial cells and surrounding support cells.102,103 Conversely, Ang-2 leads to destabilization of vessels and dissociation of pericytes, and is upregulated by hypoxia and angiogenic cytokines, including VEGF.144,170 Thus, the precise balance of VEGF and the angiopoietin/Tie-2 system is essential for modulating growing vessels and maintaining the integrity of existing vessels, and determining if vessels proliferate or become leaky. In 2005, Mohan et al155 studied indices of angiogenesis based on the plasma levels of Ang-1 and Ang-2 and their soluble receptor Tie-2, and the levels of VEGF and its soluble receptor Flt-1 and levels of vWF (which indicate endothelial damage and dysfunction). SCD patients with PSR were compared to those with nonproliferative retinopathy or no retinopathy and to

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normal controls. Plasma levels of angiopoietins, VEGF and vWF were elevated in SCD patients compared to controls, but did not differ by retinopathy severity. Only limited improvement occurred after laser treatment. Thus, the role of angiopoietins and their possible interaction with VEGF in retinal neovascularization is not fully understood. In human SCD retinal tissue, Ang-2 and Tie-2 expression appears to be associated with ischemic retinal disorders,216 and VEGF expression associated with abnormal proliferation.22 Because angiogenesis is the primary pathology in PSR, the retina is an excellent model for this aspect of SCD pathophysiology. Patients with SC-type disease are at increased risk for thromboembolic complications, retinopathy, and renal papillary necrosis, compared with individuals with SS-type disease.12 Among patients with SCD attending an ophthalmology clinic, retinopathy was present in 33% of patients with Hb SC disease compared to 3% with Hb SS.134 Complete ophthalmologic examination, including fluorescein angiography, of individuals with SC in the Ivory Coast found retinal lesions in 70% of the patients. Approximately 49% had nonvasoproliferative lesions, 22.7% had proliferative lesions, and 2.7% had neovascular lesions.51 Although this may be partially to the result of the benign nature of the systemic disease and the longer lifespan of these individuals, the constellation of high hematocrit levels, increased cell density, greater blood viscosity and lower Hb F levels in individuals with SC-type disease may contribute to the development of the proliferative changes. An additional factor may be that high VEGF levels in SS are counterbalanced by high levels of thrombospondin,19 whereas elevated levels of VEGF in Hb SC are unaffected because of low TSP levels.19,209

flow, platelet activation, increased endothelin-1 expression, and end-organ injury. Although NO is difficult to administer, its precursor, L-arginine, is available as an oral supplement, and its administration is known to induced NO production and reduce red cell density in transgenic sickle cell mice.225,231 Vasospasm is thought to play an important role in the pathophysiology of SCD. Nifidipine treatment of sickle cell crisis leads to reversal of ischemic retinal and conjunctival changes, as well as a significant improvement in color vision.187

4. Nitric Oxide Dysregulation

B. ANTERIOR SEGMENT CHANGES

NO is a critical factor in the pathophysiology of SCD and a promising antisickling agent because of its vasodilatory properties. It regulates blood vessel tone, endothelial adhesion, as well as the severity of ischemia-reperfusion injury and anemia in SCD. SCD is associated with steady-state increases in plasma cell-free Hb, and overproduction of reactive oxygen species. These factors, as well as others, scavenge endothelium-derived NO and metabolize its precursor arginine, impairing NO homeostasis. Overproduction of reactive oxygen species such as superoxide by enzymatic and non-enzymatic pathways promotes intravascular oxidative stress that also disrupts NO homeostasis. Reduced NO bioavailability is associated with vasoconstriction, decreased blood

One of the earliest reported findings in SCD was transient saccular and sausage-like dilatations of conjunctival vessels that were packed with red cells.37 Paton173 described these comma-shaped capillary segments in the inferior bulbar conjunctiva as pathognomonic of SCD, calling them the ‘‘conjunctival sign.’’ He observed that these abnormal vessels varied in number between patients, were more common in SS than in SC disease, were uncommon in patients with high Hb F levels, and their pattern was unchanged by inhalation of 95% oxygen but diminished rapidly under heat from a slit lamp beam. These findings led to the suggestion that these abnormalities were related to the degree of sickle cell formation in individual

III. Ocular Manifestations of Sickle Cell Disease Almost any ocular tissue can be affected by SCD, and the eye provides a unique opportunity for direct observation of the SCD vaso-occlusive process. Reviews on the ocular features of SCD are available,65,134,166 and an update of the clinical features, pathobiology, and management is detailed herein. A. RETROBULBAR AND ORBIT INVOLVEMENT

Patients with SCD are predisposed to both orbital wall infarction and orbital cellulitis and both present as orbital compression syndrome with inflammation. Orbital changes are usually confirmed using magnetic resonance imaging with contrast. All patients should be started on empirical intravenous antibiotics.70 Orbital compression syndrome characterized by facial pain, fever, lid edema, and proptosis has also been attributed to hematomas adjacent to orbital bones or in the retrobulbar space,40,182,205 and sudden permanent unilateral loss of vision in a SCD patient without demonstrable retinal arterial changes to retrobulbar ischemic neuropathy.180 Recurrent bilateral lacrimal gland enlargement has also been reported.3

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patients.174 Reduced hemoglobin and increased hematocrit values are added risk factors for these vascular changes.129 Similar segmentation of the blood column was observed in the optic nerve head of patients with a sickle hemoglobinopathy and called the ‘‘disc sign.’’199 Pathophysiological studies demonstrated that conjunctival vessels constrict during painful crisis phase, with blood flow returning to normal on recovery.60 A concomitant fall in conjunctival oxygen tension without change in conjunctival temperature also occurs during the crisis.106 Conjunctival blood flow improves following transfusion, and the number of conjunctival vessel abnormalities decreases with local heat, partly because of generalized vasodilatation. Abnormalities increase with vasoconstrictor drops, with the effects more apparent in children than adults.60 Fluorescein angiographic studies of the conjunctiva have shown faster circulation times in SS disease,154 so abnormalities likely reflect the obstruction of flow by sickled or less deformable cells. Conjunctival signs were found in approximately half of the SCD patients in a study in Lagos,7 and the authors concluded that conjunctival abnormalities were common, whereas PSR was rare in their patients. Anterior segment ischemia is a potentially devastating complication that mainly occurs following treatment of retinal detachment (RD) and vitreous hemorrhage caused by PSR by scleral buckling and pars plana vitrectomy. Statistics from the 1970s suggested that this was a common complication in SC type disease.108,192 Fortunately, this complication has been reduced significantly with current surgical techniques. Anterior segment ischemia may also occur in SCD patients who undergo vitrectomy without scleral buckling, if pan retinal photocoagulation is extensive.126 Sectoral iris atrophy, pupillary irregularity, and atrophic patches on the iris may result from iris infarcts, or occasionally, a limited form of spontaneous anterior segment ischemia1,25,69 In addition, PSR can proceed to rubeosis iridis, although this is rare.88 Erythrocyte-induced glaucoma may occur in SCD following traumatic or post-surgical hyphema. The pathogenesis is probably mechanical, because deformed and less pliable sickled cells are unable to pass through the 0.3--2 mm pores of the trabecular meshwork.14,88 In SCD patients, even modest elevations of intra-ocular pressure after hyphema are frequently associated with visual loss caused by central retinal artery occlusion.83--86 Therefore, hyphema in SCD patients should be considered an emergency and an indication for intensive medical therapy or early surgical intervention.42 Neovascular glaucoma is a rare complication of PSR, but most antiglaucoma medications have a narrow margin of

safety in SCD patients.30 Intracameral tissue plaminogen activator is useful for treating post-traumatic hyphema and secondary glaucoma in SCD,112 and transcorneal oxygen therapy is reported to be successful.13 C. POSTERIOR SEGMENT DISEASE

The tortuosity of major retinal vessels is attributed to arteriovenous anastomoses228 in the retinal periphery, and is reported for a majority of patients with the SS genotype, less frequently for other genotypes. Welch and Goldberg228 found significant venous tortuosity in 47% of SS patients and 32% of SC patients, and Condon and Serjeant33,34 reported an 11% incidence for each genotype. However, the interpretation of these figures is complicated by the lack of a precise definition of tortuosity. In SCD, retinal vascular occlusions typically occur in the peripheral retina, where the vessels may terminate abruptly as hairpin loops.150 Only arterioles and capillaries are occluded in children, whereas both arteries and veins occlude in adults, possibly because sRBCs are the only insult in children, but leukocyte and endothelial activation over time causes additional symptoms in adults.148 Another reason for this difference may be because the adult vascular bed experiences cumulative damage as the result of repeated insults due to the longer duration of the disease whereas children presumably have had fewer insults. Similarly, vascular occlusions in the posterior pole, such as branch retinal artery occlusion and submacular choroidal infarction, are more common in adults.77,81 Spontaneous central retinal artery occlusion or major quadrantic branch occlusion occur in SC-type disease,59 but have also been reported in young patients with SS disease.109,145 Central retinal artery occlusion has also been reported following retrobulbar anaesthesia.118,189 Although the central retinal artery may reperfuse soon after the procedure, the inner retina may become atrophic and the disk become pale. Visual prognosis depends on the duration and site of the ischemia, but is generally poor. The precapillary arterioles are predominantly involved in retinal vascular occlusion, rather than the capillaries and veins. In SCD, these obstructions are believed to involve several mechanisms, including aberrant endothelial adhesion by sickled erythrocytes, coagulation activation, thrombosis of the vasa vasorum, and secondary intimal proliferation.59 Reduced bioavailability of NO also causes vasoconstriction, decreased blood flow, platelet activation, and increased endothelin-1 expression, resulting in further injury to precapillary arterioles.

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These arteriolar obstructions result in ischemic involution of the dependent capillary bed and may explain the sickling maculopathy. The tendency of arteriolar obstruction to occur in the periphery and macula may also be because the ratio of retinal tissue to vascular compartment is greater in areas with a single-layer capillary bed, which are more prone to hypoxic insults than other areas of the retina. Lutty137 hypothesized that, in SS, the full diameter of the arteriole may be occluded by trapped cells, whereas in SCD, cells with low retention and adhesive properties may have a more important role than physical obstruction. Larger diameter veins are less susceptible to trapped cells and are less affected by a reduced supply of NO. Dehydration may also precipitate retinal venous occlusion, as reported in a SCD subject after a cycling race.99 The macula may be affected by abnormal perfusion, epiretinal membranes, schisis, holes, and rarely, posterior pole neovascularization. Small vessel obstruction with remodeling of the arcades around the foveal avascular zone (FAZ) is common.9,87 Abnormalities in the fine vasculature of the macular and perimacular regions were reported in 7 of 35 consecutive patients,211 and in 29 of 100 patients with SCD.9 There was a significant difference in FAZ median size 1.0 mm for SCD patients compared to 0.6 mm for normal controls. Within the sickle cell group, FAZ diameters did not vary significantly with degree of retinopathy, type of sickle hemoglobinopathy, or visual acuity.195 Counts of perimacular vascular abnormalities are inversely related to FAZ size,146 suggesting that these vascular anomalies are a consequence of vaso-occlusive episodes that progress to ischemia and formation and enlargement of the FAZ. Roy et al190 demonstrated that at the macula, leukocyte velocity, and hence blood flow, are inversely related to red cell density, which is consistent with dense red cells impairing macular perfusion. However, whether capillary loss is gradual and progressive, or occurs by intermittent acute events, is unknown. Multiple cotton wool spots associated with extensive capillary loss have been described in a patient without visual symptoms.7 Goldbaum80 described a ‘‘retinal depression sign’’ to indicate a retinal infarct, but macular infarcts can now be confirmed by optical coherence tomography.230 Undoubtedly, macular ischemia can occur, but the peripheral ischemia is much more prominent, and this contributes to the different locations of neovascularization seen with sickle cell disease or diabetes. The functional consequences of macular changes are uncertain. Loss of central visual function is variable,193,211 and no close relationship exists

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between the extent of macular avascular change and visual acuity.87,146 Both abnormal color vision and central scotomas have been reported with SCD.125,191 Epiretinal membranes have been recorded in approximately 4% of eyes in patients with either SStype or SC-type disease. Reported risk factors are the presence and extent of PSR, vitreous hemorrhage, and prior laser therapy and surgery. 23,159 Successful therapy for PSR lesions reduces the frequency of epiretinal membranes.159 Epiretinal membranes may result in macular pucker, macular holes, and macular detachment.23,147,159,184 Exudative retinal detachment has also been reported in hemoglobin SC disease.47 Schubert197 reported two cases of retinoschisis in SCD patients and Raichand184 described a single case of retinoschisis in a series of 500 patients. In SCD, schisis is related to chronic low-grade ischemia of the inner nuclear layer, which houses the Mu¨ller cells, the structural backbone of the retina.188 Because the SS genotype produces chronic lowgrade ischemia, it may lead to schisis, epiretinal proliferation, and, eventually, traction on the inner layer. In contrast, rapidly progressive PSR results in traction detachment, because the resulting weakening of the intraretinal cohesive forces is insufficient to permit schisis.57 Macular holes are rare in sickle cell retinopathy. In a study of 500 sickle cell patients, Raichand et al184 found four with macular holes, and Mason147 described one successfully treated case. All cases showed evidence of peripheral PSR and epiretinal membranes that caused traction on the macula. In the case reported by Mason, the hole was elongated in the temporal-nasal direction with a prominent epiretinal membrane at the temporal aspect of the macula. Removal of the membrane resulted in hole closure. All cases reported by Raichand et al184 had SC-type disease, PSR, and epipapillary fibroglial tissue proliferation, and three had undergone photocoagulation treatment. Another possible mechanism of macular hole formation may be occlusion of perifoveal capillaries with consequent local ischemia that leads to retinal atrophy, thinning, and hole formation. Several reports have clearly demonstrated the occurrence of microvascular occlusion around the fovea.7,214 On rare occasions, retinal new vessels develop at the posterior pole in SCD, with such lesions reported to have arisen from the disk margin32 and in the perimacular area.64 The reason for different effects at the macula and the peripheral retina are unknown. Dizon et al44 described a case of posterior ciliary artery occlusion in an SCD patient, with wedgeshaped choroidal infarcts that spared the nasal long

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posterior ciliary artery. Pathological examinations of two other patients were compatible with choroidal ischemia. These areas may be predisposed to choroidal neovascularizaion.139 Previously, ‘‘disk signs’’ were described as punctate red dots on, or close to, the optic disk in SCD patients34,78,89,117 but these lesions seem to be clinically irrelevant. Disk neovascularization may occur in PSR.38,117 The association between angioid streaks, or breaks in the Bruch’s membrane, and SCD is well documented28,37,71,167 and was first described by Goodman et al in 1957.89 Angioid streaks are most common in SS disease, and their incidence in an unselected population of SCD patients was estimated to be 1--2%, although a definite relationship with age was observed.28,37 In a study of Jamaican patients, Condon and Serjeant37 reported that 22% of 60 homozygous patients over 40 years of age had angioid streaks, compared to only 2% of 150 younger patients. Clarkson28 observed angioid streaks in 2 (1.3%) out of 150 SC patients, and noted development of angioid streaks in 5 patients, aged 25--68 years, during follow-up. Streaks were found in both SS and SC patients, with an overall incidence of 7.2% for all patients, and 27% for patients over the age of 50. The clinical course of angioid streaks in sickle patients is relatively benign, and two morphological patterns are recognized. In one, the only finding is narrow dark lines radiating from the disk margin. In the other, surrounding atrophic areas are also observed. The latter is associated with recurrent hemorrhage and exudative macular changes.203 Progression of angioid streaks to macular involvement with disciform degeneration, however, was observed in only two Jamaican subjects when they reached 44 and 47 years old, although subretinal neovascularization with visual impairment has also been reported in a 21-year-old.160 The etiology of angioid streaks in SCD is unknown. Streaks occur in pseudoxanthoma elasticum as part of widespread elastic tissue degeneration. Skin biopsies of affected SS patients failed to reveal any evidence of this condition.92 Progression of elastic tissue degeneration, which is common with advancing age, could explain the apparent progression of angioid streaks in patients followed over a long period, but the nature of the initial insult remains unknown. No evidence has been found for a genetic association between pseudoxanthoma elasticum and the sickling syndromes. The occurrence of angioid streaks in other hematological disorders152,206 has led to suggestions of abnormal iron deposition in Bruch’s membrane,167 but one pathological study revealed no iron, although

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calcification was heavy.4 Elastic tissue injury has been suggested to be the result of an oxidative process, induced by the combined and interactive effects of different factors.4 The activation of polymorphonuclear neutrophils and monocytes, and increased levels of neutrophil elastase and circulating cytokines, may also contribute to tissue injury in SCD subjects. Choroidal neovascularisation (CNV) may occur spontaneously,128 but usually follows breakdown of Bruch’s membrane by high-energy laser burns.32,67,227 Two different patterns are recognized angiographically: chorioretinal neovascularization that remains in the plane of the retina and is benign, and choroidal-retinal-vitreal neovascularization that may be associated with vitreous hemorrhage, posterior hyaloid fibrosis, tractional retinal detachment, and visual loss.24,38,43,61 Choroidal infarcts may predispose to CNV, and idiopathic choroidal polypoidal vasculopathy has also been reported with sickle cell retinopathy.208 Laser photocoagulation of these lesions is considered unsuccessful,2 but these lesions may respond well to antiVEGF therapy.207 Talbot et al220 have described discrete patches of retinal discoloration that are associated with normal angiograms, but more common in patients with retinal capillary closure. Hemorrhage into the peripheral retina is common, with preretinal hemorrhages appearing as circumscribed red lesions between the sensory retina and the internal limiting membrane, in front of the retinal vasculature. These are termed salmon patch hemorrhages because of their color, and leave mottled brown areas and refractile iridescent deposits after they resolve.33,66 In contrast, intraretinal hemorrhage may resolve to a schisis cavity with iridescent deposits.57 Histologically, these deposits contain hemosiderin-laden macrophages.188 Intraretinal hemorrhages may track into the subretinal space, eliciting a retinal pigment epithelium reaction with stellate and spiculate hyperpigmentation known as a ‘‘black sunburst sign.’’201 On rare occasions, the damage from deep retinal hemorrhage may be extensive enough to cause defects in the Bruch’s membrane and the development of spontaneous chorioretinal neovascularization.128 Sunburst sign is also postulated to represent choroidal ischemic damage to the retinal pigment epithelium.49 The development of arteriolar occlusion and capillary loss at the retinal periphery is the most striking feature of ocular involvement in SCD. It is common even in young children220 and is generally more marked on the temporal side. With advancing age, a general progression of occlusion and ischemia may occur, extensive remodeling of the peripheral

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vasculature is noted, and eventually avascular and vascular areas of the retina become clearly defined.68 Abnormal arteriovenous communications develop at the border, and from these abnormal vessels, PSR lesions may develop.57,150 Vaso-occlusion progression causes the peripheral vascular arcades to move posteriorly, reaching or even passing the equator. This progression occurs most rapidly in children and adolescents, with rapid change unusual in adults. The risk factors for closure in SS disease are a low total hemoglobin, low Hb F, and high irreversibly sickled cell count.218,219 The functional effects of peripheral retinal vessel disease in the absence of PSR are unclear, although electroretinograms are frequently abnormal,176 and the abnormalities correlate with the extent of retinal non-perfusion.177 In 2007, Cusick et al41 reported a case of binasal visual field defects in a 21-year-old patient, which subsequently were found to be caused by simultaneous bilateral macular occlusive events. D. PROLIFERATIVE SICKLE RETINOPATHY

In proliferative sickle retinopathy (PSR), lesions develop in the areas of abnormal arteriovenous communications at the border between the vascular and avascular retina, usually at the temporal periphery, and develop posteriorly, with regression of the vascular arcades. In 1971, Goldberg proposed a classification system for PSR (Table 1).82 Subsequently, the authors of the Jamaican cohort study who performed annual ocular examination and fluorescein angiography on all subjects from 1973 to 1981, suggested a new classification for peripheral retinal vascular changes in SCD, based on the angiographic appearance of the retinal border. Three types were included.178 Type I is qualitatively normal, but may be posteriorly displaced with manifest loss of the capillary bed. Type II is qualitatively abnormal, with abrupt termination of small- or medium-caliber vessels. This type is further subdivided into Type IIa, which has an unstable border with capillary stumps extending into nonperfused retina, and Type IIb, which may show major recession but with a continTABLE 1

Classification of Proliferative Sickle Retinopathy Stage I Stage II Stage III Stage IV Stage V

Peripheral arterial occlusion Peripheral arteriovenous anastomoses (hair-pin loop) Neovascular and fibrous proliferations (sea fan) Vitreous hemorrhage Retinal detachment

Data compiled from Goldberg.81,82

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uous border without capillary stumps. Finally, Type III is indeterminate because recent acute arteriolar occlusion involving the vascular border gave rise to a type II pattern that reverted to normal following subsequent reperfusion of the vascular bed. Variable amounts of white fibrous tissue are associated with the vascular component. Large fibrovascular lesions, especially when located temporally, may exert considerable traction on the retina, causing RD, schisis, or macular holes.23,147,159,184 1. Incidence and Prevalence The prevalence of PSR is higher in the two mildly affected genotypes, SC and S-b thalassemia, and rises with age more steeply in the SC genotype than the SS genotype. Talbot et al218 reported the youngest case of PSR, in an 8-year-old patient with the SC genotype, and Kimmel et al115 reported a 13-year-old patient with PSR and the SS genotype. The peak prevalence of PSR in SS patients occurs between 25 and 39 years in both men and women, whereas in the SC genotype it occurs earlier, from 15--24 years in men and 20--39 years in women. The SC genotype has an earlier onset, and an earlier and higher peak incidence of PSR than the SS genotype. 2. Risk Factors In addition to the effects of genotype, age, and sex, PSR is affected by several hematological risk factors.186 Fox et al62 investigated these factors in a Jamaican cohort study and concluded that, in the SS genotype, the risk factors associated with PSR are a high total hemoglobin in males and a low fetal hemoglobin in both sexes, whereas for the SC genotype, the risk factors are increased mean cell volume and low fetal hemoglobin for both sexes, and high total hemoglobin and high mean corpuscular hemoglobin concentration in men. In the same study, the development of PSR was always associated with an unstable type IIa border. 3. Location In the Jamaican cohort study, bilateral PSR occurred in 49% of SS patients and 70% of SC patients,62 with the interval between involvement of the first and second eyes generally exceeding 1 year. Neovascularization was observed more frequently in the temporal quadrants than in the nasal quadrants, with the superotemporal quadrant considered the most common location for early neovascular proliferation. In one study, more than 93% of the eyes examined showed some temporal neovascularization on first observation of retinal neovascularization.27 Posterior pole neovascularisation has also been reported in SC-type disease.64

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4. Natural History of PSR Lesions Proliferative disease usually progresses by increases in the number or size of existing neovascular lesions,82 with each sea fan formation appearing to result from several simultaneous neovascular events. The rates of progression vary markedly between individuals.36 Condon and Serjeant described 11 new PSR lesions that developed in one patient in over 18-month period, whereas another showed gradual enlargement of a single lesion over 6--8 years. Progression is more frequent in young patients. The same authors found a mean increase of 4.8 PSR lesions/patient in SS patients under 25 years, compared to 1.9 lesions/patient in subjects over this age. Corresponding figures for patients with SC-type disease were 3.2 lesions/patient for those under 25, and 2.1 lesions/patient for patients over 25.38 Visual loss is surprisingly infrequent in SCD, in spite of these rates of progression. This may be partly explained by the frequency of spontaneous regression through the development of atrophic or autoinfarcted lesions, which is recognized as a frequent and important determinant of the natural history of PSR. Regression has been documented by serial angiography 38,149,168 and is more common in SS-type than in SC-type disease.38 Probable mechanisms that contribute to spontaneous regression include changes in pigment epithelial growth factor (PEDF)/VEGF regulation.114 Regression may explain the unexpectedly high frequency of PSR in otherwise benign genotypes of SCD. Although most patients with the SC genotype have a mild systemic clinical course with near normal hematology and infrequent vaso-occlusive episodes, patients with the SS genotype generally have frequent vaso-occlusion and a severe clinical course, yet significantly less PSR. One hypothesis to explain this observation envisaged three models with different vaso-occlusive tendencies.52 Patients with low vasoocclusive indices are unlikely to develop retinal ischemia and therefore lack the stimulus to develop PSR. Patients with moderate vaso-occlusive indices develop peripheral retinal closure and proceed to develop preproliferative or proliferative disease. Patients with high vaso-occlusive indices develop extensive peripheral retinal vascular closure, providing the stimulus for PSR formation, but proceed to occlude preproliferative arteriovenous anastomoses or nascent PSR. SC-type disease was proposed to represent the intermediate model, with vaso-occlusion sufficient to produce retinal ischemia, but insufficient to occlude the developing PSR lesions. Clinical vitreous hemorrhage occurs more commonly in the SC genotype (23%) than the SS genotype (3%). Other risks of recurrent vitreous hemorrhage include more than 60 degrees of circumferential

retinal neovascularisation, and initial presentation with vitreous hemorrhage.31 The implication of VEGF/PEDF as a pathogenetic mechanism in SCD is not as clearly understood as in other retinal vascular diseases. In vitro studies suggest that hypoxia induces upregulation of VEGF expression.6,204 However, Cao et al found that of the entire sickle cell retina, the non-perfused peripheral area had the lowest VEGF immunoreactivity, and showed less immunoreactivity than control retinas, suggesting VEGF upregulation might not occur in the sickle cell retina. The border area, which is assumed to be hypoxic, had VEGF immunoreactivity comparable to the well-perfused central areas of the same retinas.20 The authors suggested that the VEGF and bFGF immunoreactivity associated with sea fan formations may not be produced in a paracrine manner by the adjacent, hypoxic sensory retina, as has been demonstrated for diabetic retinopathy and venous occlusion, but in an autocrine manner instead. Mathews et al concluded that adhesion molecules might play an important role in the vaso-occlusive phase of sickle cell retinopathy, and in autoinfarction of sea fan formations.151 Recently, Kim et al reported that changes in VEGF and PEDF are minimal before proliferative changes occur in the sickle cell retina. However, although both PEDF and VEGF are significantly elevated in viable sea fan formations in SCD, only PEDF is present in non-viable sea fans, demonstrating that PEDF might play an important role in inhibiting angiogenesis and inducing sea fan regression. So progression of angiogenesis may depend on the PEDF/VEGF ratio.114 The principal mechanism by which PSR affects vision is through vitreous hemorrhage and retinal detachment. A study of PSR development demonstrated a moderate risk of vitreous hemorrhage (5.3%) and macular lesions (4.6%), and a low risk of retinal detachment (2%) after a mean follow-up of 6.3 years.27 Moriarty et al followed 120 patients with SS-type disease and 222 patients with SC-type disease over a period of 10 years. Visual acuity loss (less than or equal to 6/18 Snellen) attributable to sickle cell retinopathy occurred in 10% of untreated eyes. Visual loss was strongly associated with PSR, and most commonly resulted from vitreous hemorrhage, traction retinal detachment and epiretinal membranes. The incidence of visual loss was 0.031 eyes/year among patients with proliferative disease compared to 0.014 eye/year among patients with non-proliferative disease.158

IV. Pathophysiology-based Drug Treatment Prevention of eye-related complications may be achieved through novel drugs that focus on disease

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Surv Ophthalmol 55 (4) July--August 2010 TABLE 2

Summary of Some of the Emerging Therapeutic Options for SCD 1. Augmentation of Hb F a. Hydroxyurea b. Omega 3 fatty acids c. Erythropoietin d. 2-deoxy 5-azacytidine 2. Red cell hydration a. Clotrimazole b. Magnesium pidolate 3. Antiadhesive agents/antiinflammatory agents a. Antiadhesion antibodies b. Anti integrin antibodies c. AntivWF factor d. Sulphsalazine e. Statins 4. Antioxidative therapy a. Glutamine b. Deferiprone 5. Antithrombotic agents a. Heparin b. Ticlopidine c. Warfarin 6. Vasodilation a. Nitric oxide b. Arginine c. Flocor 7. Decrease Hb S cells a. Transfusion b. Pharesis 8. Transplantation of hemopoietic stem cells and gene therapy Most of these drugs have multiple actions,141 and therefore are classified by their presumed main action. Data compiled from Gupta et al,90 Hamilton et al,92 and Hankins and Aygun.93

pathobiology (Table 2). The multifaceted pathophysiology of SCD provides an opportunity to interrupt the disease at multiple sites, including polymerization of Hb S, erythrocyte density, and cell--cell interactions. For example, inducing higher levels of Hb F disrupts the pathology-initiating step of Hb S polymerization. Improving the hydration of sickle erythrocytes might counteract the endothelial, inflammatory, and oxidative abnormalities of SCD. A therapeutic approach that targets several sites of pathobiology might be the most promising. Hydroxyurea (HU) is used to increase Hb F synthesis; however, its clinical efficacy cannot be explained solely by its ability to enhance Hb F expression. Lanaro et al121 determined the plasma levels and leukocyte gene expression levels of inflammatory mediators in healthy controls, steady-state SCD patients, and SCD patients on HU therapy. They found that HU therapy was associated with a significant reversal of augmented TNF-a and, interestingly, increased plasma anti-inflammatory IL-10. Expression of IFN-gamma, IL-10, cyclooxygenase 2, and inducible NO were unaltered

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in SCD mononuclear cells, but expressions of TNF-a, IL-8, and the protective enzyme heme oxygenase-1 were significantly higher. In addition, Brun et al showed that HU downregulates endothelin-1 gene expression in cultured human endothelial cells.20 Omega-3 fatty acids have also shown promise in effectively and safely inhibiting the adhesion of leukocytes to other blood cells and to the endothelium.141 The ophthalmologic effects of orally administered Nifedipine, a calcium-channel blocker that induces vasodilatation, were monitored in 11 steady-state patients, to test the hypothesis that microvascular blood flow obstruction arteriole level is a factor for individuals with sickle cell anemia. Three patients with evidence of acute peripheral retinal arteriolar occlusion displayed a prompt reperfusion of the involved segment after treatment. Two other patients showed fading of retroequatorial retinal lesions. Color vision performance improved in six of the nine patients tested. The majority of patients also demonstrated a significant decrease in blanching of the conjunctiva, which reflects improved blood flow to this frequently involved area. No improvements were observed in a control group of stable untreated SCD subjects. These findings support the hypothesis that inappropriate vasoconstriction or frank vasospasm may be a significant factor in the pathogenesis SCD microvascular lesions, and that the selective inhibition of micovascular entrapment may be an additional strategy for managing this disorder.187 AntiVEGF agents have shown promise for the treatment of age-related macular degeneration, diabetic retinopathy, and other retinal vascular conditions, but their role in treating SCD lesions has yet to be fully investigated. Two case reports describe the complete regression of retinal neovascularization and resolution of vitreous hemorrhage following the intravitreal injection of bevacizumab.202,207 However, whether antiVEGF therapy would affect the long-term history and prognosis of the disease and the incidence of future complications is not yet known.

V. Treatment Options and Complications A. OBSERVATION

Current evidence indicates that no active interventions are required for new vessels that are asymptomatic or not threaten the macula. Longitudinal observations of a cohort of patients followed from birth to 20 years show that spontaneous regression occurred in 32% of PSR-affected eyes. Permanent visual loss was uncommon in subjects observed up to the age of 26 years.45

SICKLE CELL DISEASE AND THE EYE B. PHOTOCOAGULATION

Before retinal peripheral destructive therapies were shown to influence indirectly the proliferating capillary structures by suppressing vascular growth factors, all PSR treatment modalities rendered lesions avascular by occluding the feeding arterioles. These therapies include cryotherapy, diathermy, and feeder vessel photocoagulation, but complications limited their effectiveness.30,35,75,124 The currently recommended therapy is scatter photocoagulation, the objective of which is similar to that for diabetic retinopathy because it destroys the ischemic retina that is responsible for the proliferative retinopathy.107,117 Two retinal ablation techniques have been proposed for PSR therapy, sectoral94,185 and circumferential.39,116 In a study of 174 eyes, sectoral ablation showed a significant reduction in vitreous hemorrhage and visual loss, with no complications.56 However, retinal breaks, anterior segment ischemia, and acute choroidal ischemia have been observed with pan-retinal photocoagulation in SCD.76,110 Seiberth used a transscleral diode laser to treat a case of PSR and observed complete recession of neovessels and absorption of the vitreous hemorrhage with no side effects over a 22-month follow-up.198 Sayag et al compared the clinical outcome of stage III PSR treated with peripheral scatter photocoagulation to the natural course of the disease.196 Of 202 eyes from 101 enrolled patients, 73 showed stage III PSR, which the authors subdivided into five new grades (A, B, C, D, E) based on size, presence of hemorrhage, fibrosis, and visible vessels. After a mean follow-up of 4 years, no significant differences were seen between 38 treated eyes and 35 untreated eyes in cases with a flat sea fan less than one disk area (grade A), an elevated sea fan with partial fibrosis (grade C), an elevated sea fan and hemorrhage (grade B), or completely fibrosed sea fans with well-defined vessels (grade E). Nine complications (13%) were observed, but occurred only in untreated patients. The authors concluded that patients at grades A or C should not be initially treated, but observed. C. VITRECTOMY AND RETINAL DETACHMENT SURGERY

The complications that require intervention are nonclearing vitreous hemorrhage, rhegmatogenous RD, and macular holes or pucker. Indications include vision loss or a threat to vision. Buckling procedures may be required to treat rhegmatogenous RD, and in complicated cases, may be combined with vitrectomy.79 Vitrectomy may be required to treat dense vitreous hemorrhages, traction bands, or epiretinal membranes.79,97 Some

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observers in the 1970s found that anterior segment ischemia results from these procedures,126 leading to a recommendation of preoperative exchange transfusion, erythropheresis, and hyperbaric oxygen.30,47,108,192 These exchange transfusions had no clear benefits and were associated with systemic complications.17 Good visual and surgical outcomes have been reported without the use of exchange transfusion.183,229 Other recorded problems include iatrogenic retinal breaks, intraocular bleeding, secondary glaucoma, and systemic sickling. A period of careful observation should be employed before planning any surgery. With the advent of wide angle viewing systems and improvement in instrumentation, the results of vitreoretinal surgery for SCD have vastly improved. To reduce the incidence of anterior segment ischemia, recommendations from the 1970s include adequate preoperative hydration, use of local anaesthesia without epinephrine, good preoperative oxygenation, and avoidance of excessive cryopexy, excessive manipulation of the extra ocular muscle, and the use of carbonic anhydrase inhibitors or osmotic agents.192 More recent reports suggest that vitrectomy may be performed uneventfully without precautionary measures.157,183 Pulido et al reported 11 eyes with complications after treatment for PSR by vitrectomy, with or without scleral buckle.183 No cases of anterior segment ischemia occurred. Iatrogenic retinal breaks are a recognised retinal complication following vitrectomy.183,229 Recently, Williamson et al treated 27 patients who had vitreoretinal complications of sickle retinopathy (two SS and 25 SC patients), and followed them for a mean of 15.5 months.229 Ten cases, three with vitreous hemorrhage, four with tractional retinal detachment, and three with rhegmatogenous retinal detachment, were observed without surgery. Two patients demonstrated spontaneous flattening of the retina, one with tractional retinal detachment, and one with rhegmatogenous RD. Eighteen eyes had vitrectomy, seven with vitreous hemorrhage, three with rhegmatogenous RD, three with tractional RD, three with epiretinal membrane and two with macular holes. In all, 15 patients (83%) showed improved postoperative vision. Preoperative complications included a high incidence of iatrogenic retinal tears, especially around sea fan complexes during their delamination, which caused the authors to abandon this technique and replace it with segmentation of the lesions when necessary. Two patients required a repeat vitrectomy, one for recurrent vitreous hemorrhage and one for recurrent RD. Cataract formation after surgery was uncommon. In the authors’ experience, neither scleral buckling nor photocoagulation was necessary for good outcomes.

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D. GENE THERAPY AND STEM CELL ENGINEERING

SCD can be corrected in mouse models by transduction of hematopoietic stem cells with lentiviral vectors containing antisickling globin genes, followed by transplantation of these cells into syngeneic recipients.15,127,175,222 Although self-inactivating lentiviral vectors, with or without insulator elements, could provide a safe and effective treatment in humans, concerns about insertional mutagenesis remain. An ideal correction would involve gene replacement therapy in which the sickle globin gene (bs) is replaced with a normal copy of the gene (bA). Primary skin fibroblasts have been reprogrammed into embryonic stem-like cells, termed induced pluripotent stem (iPS) cells in mice,217 and subsequently in humans.132 These cells are similar to human embryonic stem cells and can be made to differentiate into cells representing all three germ layers, including transplantable hematopoietic stem cells. The innovation of reprogramming somatic cells to iPS cells provides a possible new approach for treating SCD and b-thalassemia patients. iPS cells could be made from the somatic cells of patients, and the mutation in the b-globin gene corrected by gene targeting. After differentiation into human stem cells, the corrected cells would be returned to the patient.132,153,171,233 b-thalassemia or SCD can be cured by bone marrow or cord blood transplantations if histocompatible donors are available.72,130 However, because the families of these patients are usually small, compatible donors are usually not found. Furthermore, graft versus host diseases of varying severity are common.17 Italy, Greece, and Cyprus have prevented new births with homozygous b-thalassemia by carrier screening, genetic counseling, prenatal diagnosis, and selective abortion of homozygous fetuses. Cells from the amniotic fluid or chorionic villi sampling that are used for prenatal diagnosis can be reprogrammed into iPS cells, giving the possibility of a new option in which cells are converted into iPS cells for perinatal treatment. This treatment would have the advantage of requiring many fewer cells than are required for adult and could also prevent organ damage in diseases in which injury can begin in utero or at an early age.

VI. Conclusions Significant progress has been made in understanding the pathophysiology of SCD. These findings must be translated to the manifestations of SCD

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in the eye and guide research on new modalities of treatment and prevention of ocular complications.

VII. Method of Literature Search A Medline database search was conducted using the following keywords and MESH headings: sickle cell eye disease, ocular morbidity, molecular biology of SCD, proliferative sickle retinopathy, screening for SCD, and genetics of SCD. Further articles were identified from the reference lists of the retrieved articles, as well as from relevant textbooks. Reports published only as abstracts and non-English language reports were also included.

References 1. Acheson RW, Ford SM, Maude GH, et al. Iris atrophy in sickle cell disease. Br J Ophthalmol. 1986;70:516--21 2. Acheson RW, Fox PD, Chuang EL, et al. Treatment of iatrogenic choroidal neovascularization in sickle cell disease. Br J Ophthalmol. 1991;75:729--30 3. Adewoye AH, Ramsey J, McMahon L, et al. Lacrimal gland enlargement in sickle cell disease. Am J Hematol. 2006; 81(11):888--9 4. Aessopos A, Farmakis D, Loukopoulos D. Elastic tissue abnormalities resembling pseudoxanthoma elasticum in beta thalassemia and the sickling syndromes. Blood. 2002; 99(1):30--5 5. Ashley-Koch A, Yang Q, Olney RS. Sickle hemoglobin (HbS) allele and sickle cell disease: a HuGE review. Am J Epidemiol. 2000;151(9):839--45 6. Aiello LP, Northrup JM, Keyt BA, et al. Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch Ophthalmol. 1995;113:1538--44 7. Akinsola FB, Kehinde MO. Ocular findings in sickle cell disease patients in Lagos. Niger Postgrad Med J. 2004;11:203--6 8. Aluoch JR. Higher resistance to Plasmodiumfalciparum infection in patients with homozygous sickle cell disease in western Kenya. Trap Med Int Health. 1997;2:568--71 9. Asdourian GK, Nagpal KC, Busse B, et al. Macular and perimacular vascular remodelling in sickling hemoglobinopathies. Br J Ophthalmol. 1976;60:431--53 10. Babalola OE, Wambebe CO. When should children and young adults with sickle cell disease be referred for eye assessment? Afr J Med Med Sci. 2001;30(4):261--3 11. Babalola OE, Wambebe CO. Ocular morbidity from sickle cell disease in a Nigerian cohort. Niger Postgrad Med J. 2005;12(4):241--4 12. Ballas SK, Lewis CN, Noone AM, et al. Clinical, hematological, and biochemical features of Hb SC disease. Am J Hematol. 1982;13:37--51 13. Benner JD. Transcorneal oxygen therapy for glaucoma associated with sickle cell hyphema. Am J Ophthalmol. 2000;130(4):514--5 14. Bergren RL, Brown GC. Neovascular glaucoma secondary to sickle cell retinopathy. Am J Ophthalmol. 1992;113:718--9 15. Beuzard Y. Mouse models of sickle cell disease. Transfus Clin Biol. 2008;15(1--2):7--11 16. Blei F, Fancher T, Guarini L. Elevated levels of circulating molecule of potential endothelial cell origins in sickle cell disease. Blood. 1994;84(Suppl):409 17. Bove JR. Transfusion-transmitted diseases: current problems and challenges. Prog Hematol. 1986;14:123--47 18. Brittain HA, Eckman JR, Swerlick RA, et al. Thrombospondin from activated platelets promotes sickle erythrocyte

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19. 20.

21.

22. 23. 24. 25. 26.

27. 28. 29.

30. 31. 32. 33. 34. 35. 36. 37. 38. 39.

40. 41.

adherence to human microvascular endothelium under physiologic flow: a potential role for platelet activation in sickle cell vasoocclusion. Blood. 1993;81:2137--43 Browne PV, Mosher DF, Steinberg MH, et al. Disturbance of plasma and platelet thrombospondin levels in sickle cell disease. Am J Hematol. 1996;51(4):296--301 Brun M, Bourdoulous S, Couraud PO, et al. Hydroxyurea downregulates endothelin-1 gene expression and upregulates ICAM-1 gene expression in cultured human endothelial cells. Pharmacogenomics J. 2003;3(4):215--26 Bunn HF. Disorders of hemoglobin, in Braunwald E, Isselbacher KJ, Petersdorf RG, et al (eds). Harrison’s Principles of Internal Medicine. New York, McGraw--Hill, 1987, ed 11, pp 1518--23 Cao J, Mathews MK, Mcleod DS, et al. Angiogenic factors in human proliferative sickle cell retinopathy. Br J Ophthalmol. 1999;83:838--46 Carney MD, Jampol LM. Epiretinal membranes in sickle cell retinopathy. Arch Ophthalmol. 1987;105:214--7 Carney MD, Paylor RR, Cunha-Vaz JG, et al. Iatrogenic choroidal neovascularization in sickle cell retinopathy. Ophthalmology. 1986;93:1163--8 Chambers J, Puglisi J, Kernitsky R, et al. Iris atrophy in hemoglobin SC disease. Am J Ophthalmol. 1974;77:247--9 Chang YP, Maier-Redelsperger M, Smith KD, et al. The relative importance of the X-linked FCP locus and betaglobin haplotypes in determining haemoglobin F levels: a study of SS patients homozygous for beta 5 haplotypes. Br J Haematol. 1997;96:806--14 Clarkson JG. The ocular manifestations of sickle cell disease: a prevalence and natural history study. Tr Am Ophth Soc. 1992;39:481--504 Clarkson JG, Altman RD. Angioid streaks. Surv Ophthalmol. 1982;26:235--46 Coates TD, Fisher TC, Pecsvarady Z, et al. Neutrophil deformability and FcRIII expression are decreased in sickle cell disease patients with clinically severe b globin haplotypes. 18th Annual Meeting —National Sickle Cell Disease Program 93. Philadelphia, PA, 1993, p 63a Cohen SB, Fletcher ME, Goldberg MF, et al. Diagnosis and management of ocular complications of sickle hemoglobinopathies: Part V. Ophthalmic Surg. 1986;6:369--74 Condon PI, Whitelocke RA, Bird AC, et al. Recurrent visual loss in homozygous sickle cell disease. Br J Ophthalmol. 1985;69(9):700--6 Condon PI, Jampol LM, Ford SM, et al. Choroidal neovascularization induced by photocoagulation in sickle cell disease. Br J Ophthalmol. 1981;65:192--7 Condon PI, Serjeant GR. Ocular findings in homozygous sickle cell anemia in Jamaica. Am J Ophthalmol. 1972;73: 533--43 Condon PI, Serjeant GR. Ocular findings in hemoglobin SC disease in Jamaica. Am J Ophthalmol. 1972;74:921--31 Condon PI, Serjeant GR. Photocoagulation and diathermy in the treatment of proliferative sickle retinopathy. Br J Ophthalmol. 1974;58:650--62 Condon PI, Serjeant GR. The progression of sickle cell eye disease in Jamaica. Docum Ophthalmol. 1975;39:203-10 Condon PI, Serjeant GR. Ocular findings in elderly cases of homozygous sickle cell disease in Jamaica. Br J Ophthalmol. 1976;60:361--4 Condon PI, Serjeant GR. Behaviour of untreated proliferative sickle retinopathy. Br J Ophthalmol. 1980;64:404--11 Cruess AF, Stephens RF, Margargal LE, et al. Peripheral circumferential retinal scatter photocoagulation for treatment of proliferative sickle retinopathy. Ophthalmology. 1983;90: 272--8 Curran EL, Fleming JC, Rice K, et al. Orbital compression syndrome in sickle cell disease. Ophthalmology. 1997;104: 1610--5 Cusick M, Toma HS, Hwang TS, et al. Binasal visual field defects from simultaneous bilateral retinal infarctions in sickle cell disease. Am J Ophthalmol. 2007;143(5):893--6

373 42. Deutsch TA, Weinreb RN, Goldberg MF. Indications for surgical management of hyphema in patients with sickle cell trait. Arch Ophthalmol. 1984;102:566--9 43. Dizon-Moore RV, Jampol LM, Goldberg MF. Chorioretinal and choriovitreal neovascularization. Arch Ophthalmol. 1981;99:842--9 44. Dizon RV, Jampol LM, Goldberg MF, et al. Choroidal occlusive disease in sickle cell hemoglobinopathies. Surv Ophthalmol. 1979;23:297--306 45. Downes SM, Hambleton IR, Chuang EL, et al. Incidence and natural history of proliferative sickle cell retinopathy: observations from a cohort study. Ophthalmology. 2005; 112(11):1869--75 46. Duits AL, Schnog JB, Lard LR, et al. Elevated IL-8 levels during sickle cell crisis. Eur J Haematol. 1998;61:302--5 47. Durant WJ, Jampol LM, Daily M. Exudative retinal detachment in hemoglobin SC disease. Retina. 1982;2(3): 152--4 48. Elliott L, Ashley-Koch AE, De Castro L, et al. Genetic polymorphisms associated with priapism in sickle cell disease. Br J Haematol. 2007;137(3):262--7 49. Emmerson GG, Lutty GA. Effects of sickle cell disease on the eye: clinical features and treatment. Hematol Oncol Clin North Am. 2005;19(5):957--63 50. Eruchalu UV, Pam VA, Akuse RM. Ocular findings in children with severe clinical symptoms of homozygous sickle cell anaemia in Kaduna, Nigeria. West Afr J Med. 2006;25(2):88--91 51. Fany A, Boni S, Adjorlolo C, et al. Retinopathy as a sickle cell trait: myth or reality? J Fr Ophtalmol. 2004;27(9 Pt 1): 1025--30 52. Fabry ME, Kaul DK. Sickle cell vasoocclusion. Hematol/ Oncol Clin N Am. 1991;5:375--98 53. Fabry ME, Sengupta A, Suzuka SM, et al. A second generation transgenic mouse model expressing both hemoglobin S (HbS) and HbS-Antilles results in increased phenotypic severity. Blood. 1995;86(6):2419--28 54. Fabry ME, Costantini F, Pachnis A, et al. High expression of human beta S-- and alpha-globins in transgenic mice: erythrocyte abnormalities, organ damage, and the effect of hypoxia. Proc Natl Acad Sci USA. 1992;89(24):12155--9 55. Fabry ME, Bouhassira EE, Suzuka SM, Nagel RL. Transgenic mice and hemoglobinopathies. Methods Mol Med. 2003;82:213--41 56. Farber MD, Jampol LM, Fox P, et al. A randomized clinical trial of scatter photocoagulation of proliferative sickle cell retinopathy. Arch Ophthalmol. 1991;109:363--7 57. Faulborn J, Ardjomand N. Tractional retinoschisis in proliferative diabetic retinopathy: a histopathologic study. Graefes Arch Clin Exp Ophthalmol. 2000;238:40--4 58. Ferrara N. Molecular and biological properties of vascular endothelial growth factor. J Mol Med. 1999;77:527--43 59. Fine LC, Petrovic V, Irvine AR, et al. Spontaneous central retinal artery occlusion in hemoglobin SC disease. Am J Ophthalmol. 2000;130:680--1 60. Fink AI, Funahashi T, Robinson M, et al. Conjunctival blood flow in sickle cell disease. Arch Ophthalmol. 1961; 66:824--9 61. Fox PD, Acheson RW, Serjeant GR. Outcome of iatrogenic choroidal neovascularization in sickle cell disease. Br J Ophthalmol. 1990;74:417--20 62. Fox PD, Dunn DT, Morris JS, et al. Risk factors for proliferative sickle retinopathy. Br J Ophthalmol. 1990;74: 172--6 63. Francis R Jr, Haywood LJ. Elevated immunoreactive tumor necrosis factor and interleukin-1 in sickle cell disease. J Natl Med Assoc. 1992;84:611--5 64. Frank RN, Cronin MA. Posterior pole neovascularization in a patient with hemoglobin SC disease. Am J Ophthalmol. 1979;88:680--2 65. Gagliano DA, Jampol L, Rabb M. Sickle cell disease, in Tasman WS, Jaeger E (eds). Duane’s Clinical Ophthalmology, Vol. 3. Philadelphia, Lippincott-Raven Press, 1996, pp 1--38.

374

Surv Ophthalmol 55 (4) July--August 2010

66. Gagliano DA, Goldberg MF. The evolution of salmon-patch hemorrhages in sickle cell retinopathy. Arch Ophthalmol. 1989;107:1814--5 67. Galinos SO, Asdourian GK, Woolf MB, et al. Choroido-vitreal neovascularization after argon laser photocoagulation. Arch Ophthalmol. 1975;93:524--30 68. Galinos SO, Asdourian GK, Woolf MB, et al. Spontaneous remodelling of the peripheral retinal vasculature in sickling disorders. Am J Ophthalmol. 1975;79:853--70 69. Galinos SO, Rabb MF, Goldberg MF, et al. Hemoglobin SC disease and iris atrophy. Am J Ophthalmol. 1973;75:421--5 70. Ganesh A, Al-Zuhaibi S, Pathare A, et al. Orbital infarction in sickle cell disease. Am J Ophthalmol. 2008;146(4):595--601 71. Geeraets WJ, Guerry D III. Angioid streaks and sickle cell disease. Am J Ophthalmol. 1960;49:450--70 72. Giardini C, Lucarelli G. Bone marrow transplantation for beta-thalassemia. Hematol Oncol Clin North Am. 1999;13: 1059--64 73. Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a cohort of infants with sickle cell disease: Cooperative Study of Sickle Cell Disease. Blood. 1995;86:776--83 74. Gill HS, Lam WC. A screening strategy for the detection of sickle cell retinopathy in pediatric patients. Can J Ophthalmol. 2008;43:188--91 75. Goldbaum MH, Fletcher RC, Jampol LM, et al. Cryotherapy of proliferative sickle retinopathy. II. Triple freeze-thaw cycle. Br J Ophthalmol. 1979;63:97--101 76. Goldbaum MH, Galinos SO, Apple D, et al. Acute choroidal ischemia as a complication of photocoagulation. Arch Ophthalmol. 1976;94:1025--35 77. Goldbaum MH, Goldberg MF, Nagpal K, et al. Proliferative sickle retinopathy, in L’Esperance F (ed). Current Diagnosis and Management of Chorioretinal Disease. St Louis, CV Mosby Co, 1976, pp 132--45 78. Goldbaum MH, Jampol LM, Goldberg MF. The disc sign in sickling hemoglobinopathies. Arch Ophthalmol. 1978;96: 1597--600 79. Goldbaum MH, Peyman GA, Nagpal KC, et al. Vitrectomy in sickling retinopathy: report of five cases. Ophthalmic Surg. 1976;7:92--102 80. Goldbaum MH. Retinal depression sign indicating a small retinal infarct. Am J Ophthalmol. 1978;86(1):45--55 81. Goldberg MF. Retinal neovascularization in sickle cell retinopathy. Trans Am Acad Ophthalmol Otolaryngol. 1977;83:409--31 82. Goldberg MF. Natural history of untreated proliferative sickle retinopathy. Arch Ophthalmol. 1971;85:428--37 83. Goldberg MF. Sickled erythrocytes, hyphema, and secondary glaucoma IV. The rate and percentage of sickling of erythrocytes in rabbit aqueous humor, in vitro and in vivo. Ophthalmic Surg. 1979;10:62--9 84. Goldberg MF. Sickled erythrocytes, hyphema, and secondary glaucoma I. The diagnosis and treatment of sickled erythrocytes in human hyphemas. Ophthalmic Surg. 1979;10:17--31 85. Goldberg MF. The diagnosis and treatment of secondary glaucoma after hyphema in sickle cell patients. Am J Ophthalmol. 1979;87:43--9 86. Goldberg MF, Dizon R, Raichand M. Sickled erythrocytes, hyphema, and secondary glaucoma II. Injected sickle cell erythrocytes into human, monkey, and guinea pig anterior chambers: the introduction of sickling and secondary glaucoma. Ophthalmic Surg. 1979;10:32--51 87. Goldberg MF, Galinos S, Lee CB, et al. Macular ischemia and infarction in sickling. Invest Ophthalmol. 1973;12: 633--5 88. Goldberg MF, Tso MOM. Rubeosis iridis and glaucoma associated with sickle cell retinopathy: a light and electron microscopic study. Trans Am Acad Ophthalmol Otol. 1978; 85:1028--41 89. Goodman G, Sallman L, Holland MG. Ocular manifes tations of sickle cell disease. Arch Ophthalmol. 1957;58: 655--82 90. Gupta K, Gupta P, Solovey A, Hebbel RP. Mechanism of interaction of thrompospondin with human endothelium and

ELAGOUZ ET AL

91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101.

102. 103.

104.

105. 106. 107. 108. 109. 110. 111.

112.

113.

inhibition of sickle erythrocyte adhesion to human endothelial cells by heparin. Biochem Biophys Acta. 1999;1453:63--73 Gurkan E, Tanriverdi K, Baslamish F. Clinical relevance of vascular endothelial growth factor levels in sickle cell disease. Ann Hematol. 2005;84:71--5 Hamilton AM, Pope FM, Condon PI, et al. Angioid streaks in Jamaican patients with homozygous sickle cell disease. Br J Ophthalmol. 1981;65:341--7 Hankins J, Aygun B. Pharmacotherapy in sickle cell disease---state of the art and future prospects. Br J Haematol. 2009; 145(3):296--308 Hanscom TA. Indirect treatment of peripheral retinal neovascularization. Am J Ophthalmol. 1982;93:88--91 Harlan JM. Anti-adhesion therapy in sickle cell disease. Blood. 2000;95:365--7 Hebbel RP, Osarogiagbon R, Kaul D. The endothelial biology of sickle cell disease: inflammation and a chronic vasculopathy. Microcirculation. 2004;11(2):129--51 Hebbel RP. Adhesive interactions of sickle erythrocytes with endothelium. J Clin Investig. 1997;100:S83--6 Hebbel RP. Blockade of adhesion of sickle cells to endothelium by monoclonal antibodies. N Eng J Med. 2000;342:1910--1 Hedreville M, Connes P, Romana M, et al. Central retinal vein occlusion in a sickle cell trait carrier after a cycling race. Med Sci Sports Exerc. 2009;41(1):14--8 Hirst C, Owusu-Ofori S. Prophylactic antibiotics for preventing pneumococcal infection in childrenwith sickle cell disease. Cochrane Database Syst Rev 2002;(3):CD003427 Hofricher J, Ross PD, Eaton WA. Kinetics and mechanism of deoxyhemoglobin S gelation: a new approach to understanding sickle cell disease. Proc Natl Acad Sci USA. 1974;71: 4864--8 Holash J, Maisonpierre PC, Compton D, et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science. 1999;284:1994--8 Holash J, Wiegand SJ, Yancopoloulos GD. New model for tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene. 1999;18:5356--62 Hoppe C, Klitz W, D’Harlingue K, et al. Stroke Prevention Trial in Sickle Cell Anemia (STOP) Investigators. Confirmation of an association between the TNF(-308) promoter polymorphism and stroke risk in children with sickle cell anemia. Stroke. 2007;38(8):2241--6 Hoppe C, Klitz W, Noble J, et al. Distinct HLA associations by stroke subtype in children with sickle cell anemia. Blood. 2003;101(7):2865--9 Isenberg SJ, McRee WE, Jedrzynski MS, et al. Effects of sickle cell anemia on conjunctival oxygen tension and temperature. Arch Intern Med. 1987;147:67--9 Jampol LM, Farber M, Rabb MF, et al. An update on techniques of photocoagulation treatment of proliferative sickle cell retinopathy. Eye. 1991;5(Pt 2):260--3 Jampol LM, Green JL, Goldberg MF, et al. An update on vitrectomy surgery and retinal detachment repair in sickle cell disease. Arch Ophthalmol. 1982;100:591--3 Jampol LM, Condon P, Dizon-Moore R, et al. Salmon patch hemorrhages after central retinal artery occlusion in sickle cell disease. Arch Ophthalmol. 1981;99:237--40 Jampol LM, Goldberg MF. Retinal breaks after photocoagulation of proliferative sickle cell retinopathy. Arch Ophthalmol. 1980;98:676--9 Joneckis CC, Shock DD, Cunningham ML, et al. Glycoprotein IV--independent adhesion of sickle red blood cells to immobilized thrombospondin under flow conditions. Blood. 1996;87:4862--70 Karaman K, Culic S, Erceg I, et al. Treatment of posttraumatic trabecular mashwork thrombosis and secondary glaucoma with intracameral tissue plasminogen activator in previously unrecognized sickle cell anemia. Coll Antropol. 2005;29(Suppl 1):123--6 Kato GJ, Hebbel RP, Steinberg MH, et al. Vasculopathy in sickle cell disease: biology, pathophysiology, genetics,

SICKLE CELL DISEASE AND THE EYE

114.

115. 116.

117.

118.

119. 120. 121.

122. 123. 124. 125. 126. 127.

128. 129. 130. 131. 132. 133. 134.

135.

translational medicine, and new research directions. Am J Hematol. 2009;84(9):618--25 Kim SY, Mocanu C, Mcleod DS, et al. Expression of pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) in sickle cell retina and choroid. Exp Eye Res. 2003;77(4):433--45 Kimmel AS, Magargal LE, Maizel R, et al. Proliferative sickle retinopathy under age 20: a review. Ophthalmic Surg. 1987;18:126--8 Kimmel AS, Margargal LE, Stephens RF, et al. Peripheral circumferential retinal scatter photocoagulation for the treatment of proliferative sickle retinopathy. Ophthalmology. 1986;93:1429--34 Kimmel AS, Magargal LE, Tasman WS. Proliferative sickle retinopathy and neovascularization of the disc: regression following treatment with peripheral retinal scatter laser photocoagulation. Ophthalmic Surg. 1986;17:20--2 Klein ML, Jampol LM, Condon PI, et al. Central retinal artery occlusion without retrobulbar hemorrhage after retrobulbar anesthesia. Am J Ophthalmol. 1982;93: 573--577 Knisely MH, Bloch EH, Eliot TS, Warn, et al. Sludged blood. Science. 1947;106:431--40 Konotey-Ahulu FID. The sickle cell diseases: clinical manifestations including the ‘‘sickle crisis’’. Arch Intern Med. 1974;133:611--9 Lanaro C, Franco-Penteado CF, Albuqueque DM, et al. Altered levels of cytokines and inflammatory mediators in plasma and leukocytes of sickle cell anemia patients and effects of hydroxyurea therapy. J Leukoc Biol. 2009;85(2): 235--42 Lard LR, Mul FP, de Haas M, et al. Neutrophil activation in sickle cell disease. J Leukoc Biol. 1999;66:411--5 Lasky LA. Selectins: interpreters of cell-specific carbohydrate information during inflammation. Science. 1992;258: 964--9 Lee CB, Woolf MB, Galinos SO, et al. Cryotherapy of proliferative sickle retinopathy. Part I. Single freeze-thaw cycle. Ann Ophthalmol. 1975;7:1299--308 Lee CM, Charles HC, Smith RT, et al. Quantification of macular ischemia in sickle cell retinopathy. Br J Ophthalmol. 1987;71:540--5 Leen JS, Ratnakaram R, Del Priore LV, et al. Anterior segment ischemia after vitrectomy in sickle cell disease. Retina. 2002;22:216--9 Levasseur DN, Ryan TM, Pawlik KM, et al. Correction of a mouse model of sickle cell disease: lentiviral/antisickling beta-globin gene transduction of unmobilized, purified hematopoietic stem cells. Blood. 2003;102:4312--9 Liang JC, Jampol LM. Spontaneous peripheral chorioretinal neovascularization in association with sickle cell anemia. Br J Ophthalmol. 1983;67:107--10 Lima CS, Rocha EM, Silva NM, et al. Risk factors for conjunctival and retinal vessel alterations in sickle cell disease. Acta Ophthalmol Scand. 2006r;84(2):234--41 Locatelli F. Related umblical cord blood transplantation in patients with thalassemia and sickle cell disease. Blood. 2003;101:2137--43 Lorey FW, Arnopp J, Cunningham GC. Distribution of hemoglobinopathy variants by ethnicity in a multiethnic state. Genet Epidemiol. 1996;13:501--12 Lowry WE, Richter L, Yachechko R, et al. Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc Natl Acad Sci USA. 2008;105:2883--8 Lu M, Perez VL, Ma N. VEGF increases retinal vascular ICAM-1 expression in vivo. Invest Ophthalmol Vis Sci. 1999;40:1808--12 Lutty GA, Goldberg MF. Ophalmological complications, in Embury SH, Hebbel RP, Mohandas N, et al (eds). Sickle Cell Disease: Basic Principles and Clinical Practice. New York, Raven Press, 1994, pp 703--24 Lutty GA, Otsuji T, Taomoto M, et al. Mechanisms for sickle red blood cell retention in choroid. Curr Eye Res. 2002; 25(3):163--71

375 136. Lutty GA, Merges C, McLeod DS, et al. Nonperfusion of retina and choroid in transgenic mouse models of sickle cell disease. Curr Eye Res. 1998;17(4):438--44 137. Lutty GA, Phelan A, McLeod DS, et al. A rat model for sickle cell--mediated vaso-occlusion in retina. Microvasc Res. 1996;52(3):270--80 138. Lutty GA, McLeod DS, Pachnis A, et al. Retinal and choroidal neovascularization in a transgenic mouse model of sickle cell disease. Am J Pathol. 1994;145(2):490--7 139. Lutty GA, Merges C, Crone S, et al. Immunohistochemical insights into sickle cell retinopathy. Curr Eye Res. 1994; 13(2):125--38 140. Lutty GA, Taomoto M, Cao J, McLeod DS, et al. Inhibition of TNF-alpha-induced sickle RBC retention in retina by a VLA-4 antagonist. Invest Ophthalmol Vis Sci. 2001;42(6): 1349--55 141. Madigan C, Malik P. Pathophysiology and therapy for haemoglobinopathies. Part I: sickle cell disease. Expert Rev Mol Med. 2006;8(9):1--23 142. Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antagonist for Tie-2 that disrupts in vivo angiogenesis. Science. 1997;277:55--60 143. Malave I, Perdomo Y, Escalona E, et al. Levels of tumor necrosis factor a/cachectin (TNFa) in sera from patients with sickle cell disease. Acta Haematol. 1993;90:172--6 144. Mandriota SJ, Pepper MS. Regulation of angiopoietin-2 mRNA levels in bovine microvascular endothelial cells by cytokines and hypoxia. Circ Res. 1998;83:852--9 145. Marcus RE, Bolger JP, Roderick PJ, et al. Central retinal artery occlusion in homozygous sickle cell (SS) disease. Clin Lab Haematol. 1988;10:467--70 146. Marsh RJ, Ford SM, Rabb MF, et al. Macular vasculature, visual acuity and irreversibly sickled cells in homozygous sickle cell disease. Br J Ophthalmol. 1982;66:155--60 147. Mason JO. Surgical closure of macular hole in association with proliferative sickle cell retinopathy. Retina. 2002; 22(4):501--2 148. Mathews MK, McLeod DS, Merges C, et al. Neutrophils and leucocyte adhesion molecules in sickle cell retinopathy. Br J Ophthalmol. 2002;86:684--90 149. McLeod DS, Merges C, Fukushima A, et al. Histopathologic features of neovascularization in sickle cell retinopathy. Am J Ophthalmol. 1997;124(4):455--72 150. McLeod DS, Goldberg MF, Lutty GA. Dual-perspective analysis of vascular formations in sickle cell retinopathy. Arch Ophthalmol. 1993;111(9):1234--45 151. Mehta JS, Whittaker KW, Tsaloumas MD. Latent proliferative sickle cell retinopathy in sickle cell trait. Acta Ophthalmol Scand. 2001;79:81--2 152. McLane NJ, Grizzard WS, Kousseff BG, et al. Angioid streaks associated with hereditary spherocytosis. Am J Ophthalmol. 1984;97:444--9 153. Miller CL, Imren S, Antonchuk J, et al. Feasibility of using autologous transplantation to evaluate hematopoietic stem cell--based gene therapy strategies in transgenic mouse models of human disease. Mol Ther. 2002;6(3):422--8 154. Minatoya H, Acacio I, Goldberg M. Fluorescein angiography of the bulbar conjunctiva in sickle cell disease. Ann Ophthalmol. 1973;5:908--92 155. Mohan JS, Lip PL, Blann AD, et al. The angiopoietin/Tie-2 system in proliferative sickle retinopathy: relation to vascular endothelial growth factor, its soluble receptor Flt-1 and von Willebrand factor, and to the effects of laser treatment. Br J Ophthalmol. 2005;89:815--9 156. Moore C, Ehlayel M, Leiva L, et al. New concepts in the immunology of sickle cell disease. Ann Allergy Asthma Immunol. 1996;76:385--403 157. Morgan DM, D’Amico DJ. Vitrectomy surgery in proliferative sickle retinopathy. Am J Ophthalmol. 1987;104:133--8 158. Moriarty BJ, Acheson RW, Condon PI, et al. Patterns of visual loss in untreated sickle cell retinopathy. Eye. 1988; 2(Pt 3):330--5 159. Moriarty BJ, Acheson RW, Serjeant GR. Epiretinal membranes in sickle cell disease. Br J Ophthalmol. 1987;71:466--9

376

Surv Ophthalmol 55 (4) July--August 2010

160. Moriarty BJ, Webb DK, Serjeant GR. Treatment of subretinal neovascularization associated with angioid streaks in sickle cell retinopathy. Arch Ophthalmol. 1987;105:1327--8 161. Morris CR. Mechanisms of vasculopathy in sickle cell disease and thalassemia. Hematology Am Soc Hematol Educ Program. 2008:177--85 162. Mozzarelli A, Hofricher J, Eaton WA. Delay time of hemoglobin S polymerization prevents most cells from sickling in vivo. Science. 1987;237:500--6 163. Nagel RL, Ranney HM. Genetic epidemiology of structural mutations of the beta-globin gene. Semin Hematol. 1990; 27:342--59 164. Nagel RL, Fabry ME, Steinberg MH. The paradox of hemoglobin SC disease. Blood Rev. 2003;17(3):167--78 165. Nagel RL, Fabry ME. The panoply of animal models for sickle cell anaemia. Br J Haematol. 2001;112(1):19--25 166. Nagpal KC, Goldberg MF, Rabb MF. Ocular manifestations of sickle hemoglobinopathies. Surv Ophthalmol. 1977 Mar--Apr;21(5):391--411 167. Nagpal KC, Asdourian G, Goldbaum M, et al. Angioid streaks and sickle hemoglobinopathies. Br J Ophthalmol. 1976;60:31--4 168. Nagpal KC, Patrianakos D, Asdourian GK, et al. Spontaneous regression (autoinfarction) of proliferative sickle retinopathy. Am J Ophthalmol. 1975;80:885--92 169. Nagpal KC, Asdourian GK, Patrianakos D, et al. Proliferative retinopathy in sickle cell trait. Arch Intern Med. 1977;137:325--8 170. Oh H, Takagi H, Suzuma K, et al. Hypoxia and vascular endothelial growth factor selectively upregulate angiopoietin-2 in bovine microvascular endothelial cells. J Biol Chem. 1999;274:15732--9 171. Park IH, Zhao R, West JA, et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature. 2008;451:141--6 172. Paszty C, Brion CM, Manci E, et al. Transgenic knockout mice with exclusively human sickle hemoglobin and sickle cell disease. Science. 1997;278:876--8 173. Paton D. The conjunctival sign of sickle cell disease. Arch Ophthalmol. 1961;66:90--4 174. Paton D. The conjunctival sign of sickle cell disease: further observations. Arch Ophthalmol. 1962;68:627--32 175. Pawlik R, Westerman KA, Fabry ME, et al. Correction of of sickle cell disease in transgenic mouse models by gene therapy. Science. 2001;294:2368--71 176. Peachey NS, Charles HC, Lee CM, et al. Electroretinographic findings in sickle cell retinopathy. Arch Ophthalmol. 1987; 105:934--8 177. Peachey NS, Gagliano DA, Jacobson MS, et al. Correlation of electroretinographic findings and peripheral retinal nonperfusion in patients with sickle cell retinopathy. Arch Ophthalmol. 1990;108:1106--9 178. Penman AD, Talbot JF, Chuang EL, et al. New classification of peripheral retinal vascular changes in sickle cell disease. Br J Ophthalmol. 1994;78:681--9 179. Perelman N, Selvaraj SK, Batra S, et al. Placenta growth factor activates monocytes and correlates with sickle cell disease severity. Blood. 2003;102:1506--14 180. Perlman JI, Forman S, Gonzalez ER. Retrobulbar ischemic optic neuropathy associated with sickle cell disease. J Neuro-Ophthalmol. 1994;14:45--8 181. Powars D, Hiti A. Sickle cell anemia: beta s gene cluster haplotypes as genetic markers for severe disease expression. Am J Dis Child. 1993;147:1197--202 182. Procianoy F, Branda˜o Filho M, Cruz AA, et al. Subperiosteal hematoma and orbital compression syndrome following minor frontal trauma in sickle cell anemia: case report. Arq Bras Oftalmol. 2008;71(2):262--4 183. Pulido JS, Flynn HW, Clarkson JG, et al. Pars plana vitrectomy in the management of complications of proliferative sickle retinopathy. Arch Ophthalmol. 1988;106:1553--7 184. Raichand M, Dizon RV, Nagpal KC, et al. Macular holes associated with proliferative sickle cell retinopathy. Arch Ophthalmol. 1987;96:1592--6

ELAGOUZ ET AL 185. Rednam KRV, Jampol LM, Goldberg MF. Scatter retinal photocoagulation for proliferative sickle cell retinopathy. Am J Ophthalmol. 1982;93:594--9 186. Ribeiro JA, Lucena D da R, Lucena L da R, et al. Proliferative sickle cell retinopathy associated with sickle cell trait and gestational diabetes: case report. Arq Bras Oftalmol. 2009;72(3):400--2 187. Rodgers GP, Roy MS, Noguchi C, et al. Is there a role for selective vasodilation in the management of sickle cell disease? Blood. 1988;71:597--602 188. Romayananda N, Goldberg MF, Green WR. Histopathology of sickle cell retinopathy. Trans Am Acad Ophthalmol Otol. 1973;77:652--76 189. Roth SE, Magargal LE, Kimmel AS, et al. Central retinal artery occlusion in proliferative sickle cell retinopathy after retrobulbar injection. Ann Ophthalmol. 1988;20: 221--4 190. Roy MS, Gascon P, Giuliani D. Macular blood flow velocity in sickle cell disease, relation to red cell density. Br J Ophthalmol. 1995;79:742--5 191. Roy MS, Rodgers G, Gunkel R, et al. Color vision defects in sickle cell anemia. Arch Ophthalmol. 1987;105:1676--8 192. Ryan SJ, Goldberg MF. Anterior segment ischemia following scleral buckling in sickle cell hemoglobinopathy. Am J Ophthalmol. 1971;72:35--50 193. Ryan SJ. Occlusion of the macular capillaries in sickle cell hemoglobin C disease. Am J Ophthalmol. 1974;77:459--61 194. Saleh AW, Hillen HF, Duits AJ. Levels of endothelial, neutrophil and platelet-specific factors in sickle cell anemia patients during hydroxyurea therapy. Acta Haematol. 1999; 102:31--7 195. Sanders RJ, Brown GC, Rosenstein RB, et al. Foveal avascular zone diameter and sickle cell disease. Arch Ophthalmol. 1991;109(6):812--5 196. Sayag D, Binaghi M, Souied EH, et al. Retinal photocoagulation for proliferative sickle cell retinopathy: a prospective clinical trial with new sea fan classification. Eur J Ophthalmol. 2008;18(2):248--54 197. Schubert HD. Schisis in sickle cell retinopathy. Arch Ophthalmol. 2005;123:1607--9 198. Seiberth V. Transscleral diode laser photocoagulation in proliferative sickle cell retinopathy. Ophthalmology. 1999; 106(9):1828--9 199. Serjeant GR. The Clinical Features of Sickle Cell Disease. New York, Elsevier, 1974 200. Serjeant GR, Serjeant BE. Nomenclature and genetics of sickle cell disease, in Serjeant GR, Serjeant BE (eds). Sickle Cell Disease. Oxford, Oxford University Press, 2001, ed 3, pp 31--40 201. Serjeant GR, Serjeant BE. The eyes, in Serjeant GR, Serjeant BE (eds). Sickle Cell Disease. Oxford, Oxford University Press, 2001, ed 3, pp 366--92 202. Shaikh S. Intravitreal bevacizumab (Avastin) for the treatment of proliferative sickle retinopathy. Indian J Ophthalmol. 2008; 56:259 203. Shields JA, Federman JL, Tomer TL, et al. Angioid streaks, I. Ophthalmoscope variations and diagnostic problems. Br J Ophthalmol. 1975;59:257--66 204. Shima DT, Deutsch U, D’Amore P. Hypoxic induction of vascular endothelial growth factor (VEGF) in human epithelial cells is mediated by increases in mRNA stability. FEBS Lett. 1995;370:203--8 205. Sidman JD, Brownlee RE, Smith WC, et al. Orbital complications of sickle cell disease. Internat J Pediat Otorhinolaryngol. 1990;169:181--4 206. Singerman LJ. Angioid streaks in thalassemia. Br J Ophthalmol. 1983;67:558 207. Siqueira RC, Costa RA, Scott IU, et al. Intravitreal bevacizumab (Avastin) injection associated with regression of retinal neovascularization caused by sickle cell retinopathy. Acta Ophthalmol Scand. 2006;84:834--5 208. Smith RE, Wise K, Kingsley RM. Idiopathic polypoidal choroidal vasculopathy and sickle cell retinopathy. Am J Ophthalmol. 2000;129(4):544--6

377

SICKLE CELL DISEASE AND THE EYE 209. Solovey A, Gui L, Ramakrishnan S, et al. Sickle cell anemia as a possible state of enhanced anti--apoptotic tone: survival effect of vascular endothelial growth factor on circulating and unanchored endothelial cells. Blood. 1999;93(11): 3824--30 210. Steinberg MH, Thein SL. Genetic Modulation of sickle cell disease, in Pace BS (ed). Renaissance of Sickle Cell Disease Research in the Genome Era. London, Imperial College Press, 2007, pp 193--206 211. Stevens TS, Busse B, Lee CB, et al. Sickling hemoglobinopathies. Macular and perimacular vascular abnormalities. Arch Ophthalmol. 1974;92:455--63 212. Stuart MJ, Settty BN. Sickle cell acute chest syndrome: pathogenesis and rationale for therapy. Blood. 1999;95: 1555--60 213. Sugihara K, Sugihara T, Mohandas N, et al. Thrombospondin mediates adherence of CD36þ sickle erythrocytes to endothelial cells. Blood. 1992;80:2634--42 214. Swerlick R, Eckman J, Kumar A, et al. Alpha 4 beta 1 expression on sickle reticulocytes: vascular cell adhesion molecule 1 dependent binding to the endothelium. Blood. 1993;82:1891--9 215. Taban M, Sears JE, Crouch E, et al. Acute idiopathic frosted branch angiitis. J AAPOS. 2007;11(3):286--7 216. Takagi H, Koyama S, Seike H, et al. Potential role of angiopoietin/Tie-2 system in ischemia-induced retinal neovascularization. Invest Ophthalmol Vis Sci. 2003;44: 393--402 217. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663--76 218. Talbot AF, Bird AC, Maude GH, et al. Sickle cell retinopathy in Jamaican children: fyrther observation from a cohort study. Br J Ophthalmol. 1988;72:727--32 219. Talbot AF, Bird AC, Rabb LM, et al. Sickle cell retinopathy in Jamaican children: a search for prognostic factors. Br J Ophthalmol. 1983;67:782--5 220. Talbot JF, Bird AC, Serjeant GR, et al. Sickle cell retinopathy in young children in Jamaica. Br J Ophthalmol. 1982;66:149--54 221. Thomas PW, Higgs DR, Serjeant GR. Benign clinical course in homozygous sickle cell disease: a search for predictors. J Clin Epidemiol. 1997;50:121--6 222. Townes TM. Gene replacement therapy for sickle cell disease and other blood disorders. Hematology Am Soc Hematol Educ Program;193--6

The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Reprint address: Dr. Sobha Sivaprasad DM, MS, FRCS, Consultant Ophthalmologist, Laser and Retinal Research Unit, Department of Ophthalmology, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom. e-mail: [email protected].

III. Ocular manifestations of sickle cell disease

Outline

A. B. C. D.

I. Introduction A. B. C. D.

Genetics of sickle cell disease Prevalence of sickle cell disease Genetic modifiers Genetic modifiers and ocular disease E. Animal models of sickle cell disease

Retrobulbar and orbit involvement Anterior segment changes Posterior segment disease Proliferative sickle retinopathy

1. Incidence and prevalence 2. Risk factors 3. Location 4. Natural history of PSR lesions IV. Pathophysiology-based drug treatment V. Treatment options and complications

II. Molecular biology of sickle cell disease A. Factors affecting red blood cells B. Extrinsic factors 1. Inflammation and endothelial activation 2. Pro-coagulant pathways 3. Angiogenesis 4. Nitric oxide dysregulation

223. Traore´ J, Boitre JP, Bogoreh IA, et al. Sickle cell disease and retinal damage: a study of 38 cases at the African Tropical Ophthalmology Institute (IOTA) in Bamako. Med Trop (Mars). 2006;66(3):252--4 224. Trudel M, De Paepe ME, Chre´tien N, et al. Sickle cell disease of transgenic SAD mice. Blood. 1994;84(9):3189--97 225. Vichinsky E. New therapies in sickle cell disease. Lancet. 2002;360(9333):629--31 226. Wajer SD, Taomoto M, McLeod DS, et al. Velocity measurements of normal and sickle red blood cells in the ratretinal and choroidal vasculatures. Microvasc Res. 2000; 60(3):281--93 227. Wallow IHL, Davis MD. Clinicopathologic correlation of xenon arc and argon laser photocoagulation. Arch Ophthalmol. 1979;97:2308--14 228. Welch RB, Goldberg MF. Sickle-cell hemoglobin and its relation to fundus abnormality. Arch Ophthalmol. 1966;75: 353--62 229. Williamson TH, Rajput R, Laidlaw DAH, Mokete B. Vitreoretinal management of the complications of sickle cell retinopathy by observation or pars plana vitrectomy. Eye. 2008;296:1--7 230. Witkin AJ, Rogers AH, Ko TH, et al. Optical coherence tomography demonstration of macular infarction in sickle cell retinopathy. Arch Ophthalmol. 2006;124(5):746--7 231. Wood KC, Hsu LL, Gladwin MT. Sickle cell disease vasculopathy: a state of nitric oxide resistance. Free Radic Biol Med. 2008;44(8):1506--28 232. Wun T, Paglieroni T, Field CL, et al. Platelet--erythrocyte adhesion in sickle cell disease. J Investig Med. 1999;47:121--7 233. Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917--20 234. Zimmerman SA, O’Branski EE, Rosse WF, et al. Hemoglobin S/O(Arab): thirteen new cases and review of the literature. Am J Hematol. 1999;60(4):279--84

cell

A. B. C. D.

Observation Photocoagulation Vitrectomy and retinal detachment surgery Gene therapy and stem cell engineering

VI. Conclusions VII. Method of literature search